Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same

ABSTRACT

A drug delivery system for oral administration of hydrophobic drugs with enhanced and extended absorption and improved pharmacokinetics is provided. In one embodiment, formulations comprising testosterone and testosterone esters, e.g., testosterone palmitate, are disclosed. Methods of treating a hormone deficiency or effecting male contraception with the inventive formulations are also provided.

CLAIM OF PRIORITY

This application is a continuation of U.S. non-provisional applicationSer. No. 15/723,976, filed Oct. 3, 2017, which is a continuation of U.S.non-provisional application Ser. No. 14/303,179, filed Jun. 12, 2014,which is a continuation application of U.S. non-provisional applicationSer. No. 13/553,586, filed Jul. 19, 2012, which is a continuationapplication of U.S. non-provisional application Ser. No. 11/911,446, nowU.S. Pat. No. 8,241,664, issued Aug. 14, 2012, which is a national phaseapplication of PCT/US06/14207, filed Apr. 14, 2006, which claimspriority to U.S. provisional application Nos. 60/671,454 filed Apr. 15,2005 and 60/721,971 filed Sep. 30, 2005, the disclosures of which areincorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates generally to pharmaceutical deliverysystems of hydrophobic drugs and compositions comprising same. Moreparticularly, the present invention relates to pharmaceuticalcompositions comprising testosterone and esters thereof with enhancedand extended absorption and pharmacokinetics.

BACKGROUND OF THE INVENTION

Many pharmaceutically active compounds intended for oral administrationare poorly soluble in water providing a challenge to formulate thesedrugs in a drug delivery system that exhibits the desirablepharmacokinetic profiles in vivo. Poor oral bioavailability may lead toineffective therapy, the need for higher dosing and/or undesirable sideeffects. As well, pharmaceutical preparations with relatively shorthalf-lives require frequent dosing at the expense of patientinconvenience and higher therapy costs.

Sex hormones (e.g., testosterone and its esters) are marginally watersoluble, and attempts have been made to increase their bioavailability,particularly when taken orally. However, administration of testosterone,per se, presents additional challenges. Indeed, while testosterone givenby mouth is essentially completely absorbed into the portal circulation,because of extensive first-pass hepatic metabolism, the serumconcentration of testosterone following this route of administration islow unless very large doses are administered. To overcome this problem,attempts have been made to alkylate testosterone at the C-17 position(e.g., with a methyl group to form methyltestosterone) thereby reducingmetabolism by the liver. Unfortunately, however, mere alkylation oftestosterone has not yielded desirable bioavailability and has beenassociated with potentially serious hepatotoxicity.

Other attempts have managed to increase the transient bioavailability oftestosterone and its derivatives with lipophilic solvents andsurfactants. Nonetheless, even in cases where bioavailability wasenhanced, the delivery systems failed to maintain desirable serumconcentrations over an extended period of time.

Accordingly, there is a need for a drug delivery system that can provideenhanced bioavailability of hydrophobic drugs in vivo. In addition, withrespect to testosterone therapy, there is a need for an oral drugdelivery system that may provide enhanced bioavailability oftestosterone and/or an ester thereof in vivo over an extended period oftime.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, a pharmaceutical compositionis provided comprising testosterone palmitate (TP), or a testosteroneester thereof, and two or more lipid components at least the first ofwhich comprises a hydrophilic surfactant and at least the second ofwhich comprises a lipophilic surfactant that provides for the controlledrelease of TP, said lipid components together providing for thesolubilization of TP. The pharmaceutical composition may furthercomprise at least three lipid components at least the first of whichcomprises a hydrophilic surfactant, at least the second of whichcomprises a lipophilic surfactant that provides for the controlledrelease of TP and at least the third of which comprises a lipophilicsurfactant that further provides for the solubilization of TP. As well,the pharmaceutical composition may further comprise a secondlipid-soluble therapeutic agent, such as a synthetic progestin.Formulations comprising same may be preferably in the form of an orallyactive male contraceptive.

The first lipid component may exhibit an HLB of 10 to 45, preferably 10to 30, and more preferably 10 to 20. The second lipid component mayexhibit an HLB of less than about 10, preferably less than about 7, andmore preferably less than about 5. Further, the second lipid componentmay exhibit a melting point in the range of about 25° C. to about 80°C., preferably about 35° C. to about 65° C., and more preferably about40° C. to about 60° C. The second lipid component may be chosen from thegroup consisting of stearic acid, palmitic acid, glycerol and PEG estersthereof, Precirol ATO 5 and Gelucires.

In some embodiments, the lipophilic surfactant further comprises a“sustained” or controlled-release” surfactant which may be chosen fromthe group consisting of stearic acid, palmitic acid, glycerol and PEGesters thereof, Precirol AT05, Imwitor 191, Myverol 18-06, Imwitor 370,Imwitor 375, Caprol ET, Cithrol 2MS, Marosol 183 and combinationsthereof. The hydrophilic surfactant may be a poloxyl derivative ofcastor oil. Commercially available products of this class are suppliedunder the tradenames, Cremophor or Etocas and include, Cremophor EL andRH 40 and Etocas 35 and 40. Chemophor, RH40 or Etocas 40 are preferred.

Compositions of the present invention may comprise, based on weight,10-70% a lipophilic surfactant; 1-40% a controlled release surfactant;and 5-60% a hydrophilic surfactant; and preferably 30-50% a lipophilicsurfactant; 5-25% a controlled release surfactant; and 30-40% ahydrophilic surfactant. The compositions further comprise about 5 toabout 50 percent, by weight, testosterone palmitate, preferably, about20 to about 40 percent, by weight, testosterone palmitate. The inventivepharmaceutical compositions may also comprise one or more cosolventsand/or filled into a hard or soft gelatin capsule.

In another aspect of the present invention, a method of preventing oralleviating the symptoms of testosterone deficiency in a mammaliansubject is provided comprising administering to the mammalian subject aneffective amount of testosterone palmitate (TP) solubilized in two ormore lipid components, such that the administration of said solubilizedTP raises the mammalian subject's steady state serum level oftestosterone to within those levels found in mammalian subjects havingno testosterone deficiency and providing at least some relief from suchsymptoms. In human males, the administering is preferably once or twicedaily and the mammal's steady state serum level of testosterone israised to fall within a range of about 300 ng/dl to about 1100 ng/dl.With human females, a similar dosing schedule (with a lower daily TPdose) is preferred to achieve serum testosterone levels of approximately10 to 100 ng/dl. In some embodiments, the method may raise the mammal'ssteady state serum level of testosterone by 150%, 200%, 300% or 400%.The method may further comprise administering an amount of a syntheticprogestin sufficient to inhibit gonadotropin release in said mammaliansubject and produce severe oligospermia or azospermia.

In yet another aspect of the present invention, a method of deliveringsteady-state serum levels of testosterone effective to provide at leastsome relief from symptoms of testosterone deficiency is providedcomprising solubilizing testosterone palmitate (TP) in two or more lipidcomponents at least the first of which comprises a hydrophilicsurfactant and at least the second of which comprises a lipophilicsurfactant that provides for the controlled release of TP andadministering an effective amount of the solubilized TP to a subjectsuffering from the symptoms of testosterone deficiency. The method canfurther comprise solubilizing TP in at least three lipid components atleast the first of which comprises a hydrophilic surfactant, at leastthe second of which comprises a lipophilic surfactant that provides forthe controlled release of TP and at least the third of which comprises alipophilic surfactant that further provides for the solubilization ofTP.

In further yet another aspect of the present invention, a method ofproviding extended release of testosterone in vivo is provided, themethod comprising solubilizing testosterone palmitate (TP) in a lipidmixture comprising two or more lipid components at least the first ofwhich comprises a hydrophilic surfactant and at least the second ofwhich comprises a lipophilic surfactant having a melting point ofgreater than about 35° C.

In still further yet another embodiment of the present invention, apharmaceutical composition is provided comprising testosterone palmitate(TP) and two or more lipid components at least the first of whichcomprises a hydrophilic surfactant and at least the second of whichcomprises a lipophilic surfactant, in which the at least firsthydrophilic component or the at least second lipophilic componentprovides for the controlled release of TP, and said lipid componentstogether provide for the solubilization of TP. In one embodiment, the atleast first hydrophilic component provides for the controlled release ofTP.

In this respect, before explaining at least one embodiment of theinvention in detail, it is to be understood that the invention is notlimited in its application to the details of construction and to thearrangements of the components set forth in the following description orillustrated in the drawings. The invention is capable of embodiments inaddition to those described and of being practiced and carried out invarious ways. Also, it is to be understood that the phraseology andterminology employed herein, as well as the abstract, are for thepurpose of description and should not be regarded as limiting.

As such, those skilled in the art will appreciate that the conceptionupon which this disclosure is based may readily be utilized as a basisfor the designing of other structures, methods and systems for carryingout the several purposes of the present invention. For example, someembodiments of the invention may combine TP with other active drugs,including hormonals, in an oral delivery system that, in part, preventsor alleviates symptoms associated with testosterone deficiency. It isimportant, therefore, that the claims be regarded as including suchequivalent constructions insofar as they do not depart from the spiritand scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TP,which maximizes diurnal variation while producing an early T max,preferably compatible with early morning, once-daily dosing.

FIG. 2 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TPwhich maximizes diurnal variation while producing a late T max,preferably compatible with night-time, once-daily dosing.

FIG. 3 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TPwhich provides physiological diurnal variation and an early T max,preferably compatible with early morning, once-daily dosing.

FIG. 4 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TP,which provides physiological diurnal variation and a delayed T max,preferably compatible with early morning, once-daily dosing.

FIG. 5 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TP,which provides a short elimination half-life and an early T max,preferably compatible with maximal patient activity soon after wakingand twice-daily dosing.

FIG. 6 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TP,which provides a relatively short elimination half-life and a delayed Tmax with maximal activity about waking time. One of the twice-dailydoses is preferably scheduled before bedtime.

FIG. 7 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TP,which provides and intermediate elimination half-life and a T maxpreferably compatible with maximal activity soon after walking whilereducing the extent of fluctuation to the physiological level withtwice-daily dosing.

FIG. 8 depicts a steady-state pharmacokinetic profile of the serumconcentration of testosterone upon ingestion of a formulation of TP,which provides a longer elimination half-life and a delayed T max,preferably compatible with maximal activity about awakening timefollowing bedtime administration. This formulation reduces the extent offluctuation to the physiological levels of testosterone with twice-dailydosing.

FIG. 9 shows dissolution curves of TP from three formulations (9, 23 and24 the compositions of which are listed in Table 2) in a phosphatebuffered dissolution medium incorporating TritonX-100 as a surfactant inaccordance with the present invention.

FIG. 10 shows dissolution curves of TP from three formulations (47, 50,51 and 54 the compositions of which are listed in Table 3) in aphosphate buffered dissolution medium incorporating TritonX-100 as asurfactant in accordance with the present invention.

FIG. 11 provides the mean steady-state profile of treatment with threeregimens for seven days.

FIG. 12 shows the mean steady-state serum T and DHT Levels after sevendays of BID administration of formulation 54.

FIG. 13 provides a simulated mean steady-state profile of formulation 50with respect to the observed profile for formulation 54 (bothadministered BID for seven days).

FIG. 14 shows representative in vitro dissolution profiles for variousTP formulations in phosphate buffer (PBS)

FIG. 15 shows representative in vitro dissolution profiles for variousTP formulations in fed-state simulated intestinal fluid (FeSSIF).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pharmaceutical delivery systems,preferably oral, for hydrophobic drugs. Accordingly, while the instantinvention will be described, to some extent, with reference to oraldelivery systems, the present invention may be suitable for topical andintramuscular injection. Further, hydrophobic drugs defined hereinencompass both those drugs that are inherently hydrophobic (i.e., havinga log P of at least 2) as well as otherwise hydrophilic medicaments thathave been rendered hydrophobic with suitable modification (e.g.,conjugation to fatty acids and/or lipids). (Log P is the log of theoctanol-water or buffer partition coefficient and can be determined by avariety of methods for those skilled in the art. The higher the value oflog P, the greater the lipophilicity and thus lipid solubility of thechemical entity in question.)

In one embodiment of the present invention, testosterone and/or estersat the C-17 position of the testosterone molecule, alone or incombination with other active ingredients, may be orally delivered usingthe inventive delivery system. While many of the embodiments of thepresent invention will be described and exemplified with the palmiticacid ester of testosterone (also referred to as “testosterone palmitate”or “TP”), the scope of the present invention should not be construed norlimited solely to the delivery of TP or testosterone per se. In fact, itshould be readily apparent to one of ordinary skill in the art from theteachings herein that the inventive drug delivery systems andcompositions therefrom may be suitable for oral delivery of othertestosterone esters, such as short-chain (C₂-C₆), medium-chain (C₇-C₁₃)and long-chain (C₁₄-C₂₄) fatty acid esters, preferably long-chain fattyacid esters of testosterones and numerous hydrophobic medicaments. Suchsuitable medicaments, which may be formulated in accordance with thepresent invention include, but should not be limited to, the following:

Analgesics and anti-inflammatory agents: aloxiprin, auranofin,azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofencalcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamicacid, mefenamic acid, nabumetone, naproxen, oxyphenbutazone,phenylbutazone, piroxicam, sulindac.

Anthelmintics: albendazole, bephenium hydroxynaphthoate, cambendazole,dichlorophen, ivermectin, mebendazole, nitazoxamide, oxamniquine,oxfendazole, oxantel embonate, praziquantel, pyrantel embonate,thiabendazole.

Anti-arrhythmic agents: amiodarone HCl, disopyramide, flecainideacetate, quinidine sulphate.

Anti-bacterial agents: benethamine penicillin, cinoxacin, ciprofloxacinHCl, clarithromycin, clofazimine, cloxacillin, demeclocycline,doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid,nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine,sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole,sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim.

Anti-coagulants: dicoumarol, dipyridamole, nicoumalone, phenindione.

Anti-depressants: amoxapine, maprotiline HCl, mianserin HCl,nortriptyline HCl, trazodone HCl, trimipramine maleate.

Anti-diabetics: acetohexamide, chlorpropamide, glibenclamide,gliclazide, glipizide, tolazamide, tolbutamide.

Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin,methoin, methsuximide, methylphenobarbitone, oxcarbazepine,paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide,primidone, sulthiame, valproic acid.

Anti-fungal agents: amphotericin, butoconazole nitrate, clotrimazole,econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole,ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate,terbinafine HCl, terconazole, tioconazole, undecenoic acid.

Anti-gout agents: allopurinol, probenecid, sulphin-pyrazone.

Anti-hypertensive agents: amlodipine, benidipine, darodipine, dilitazemHCl, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil,nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosinHCl, reserpine, terazosin HCl.

Anti-malarials: amodiaquine, chloroquine, chlorproguanil HCl,halofantrine HCl, mefloquine HCl, proguanil HCL, pyrimethamine, quininesulphate.

Anti-migraine agents: dihydroergotamine mesylate, ergotamine tartrate,methysergide maleate, pizotifen maleate, sumatriptan succinate.

Anti-muscarinic agents: atropine, benzhexol HCl, biperiden,ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencylcimineHCl, tropicamide.

Anti-neoplastic agents and Immunosuppressants: aminoglutethimide,amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin,dacarbazine, estramustine, etoposide, lomustine, melphalan,mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone,procarbazine HCl, tamoxifen citrate, testolactone.

Anti-protazoal agents: benznidazole, clioquinol, decoquinate,diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furzolidone,metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.

Anti-thyroid agents: carbimazole, propylthiouracil.

Anxiolytic, sedatives, hypnotics and neuroleptics: alprazolam,amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol,brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole,chlorpromazine, clobazam, clotiazepam, clozapine, diazepam, droperidol,ethinamate, flunanisonc, flunitrazepam, fluopromazine, flupenthixoldecanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam,lormetazepam, medazepam, meprobamate, methaqualone, midazolam,nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide,prochlorperazine, sulpiride, temazepam, thioridazine, triazolam,zopiclone.

Beta-blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol,nadolol, oxprenolol, pindolol, propranolol.

Cardiac Inotropic agents: amrinone, digitoxin, digoxin, enoximone,lanatoside C, medigoxin.

Corticosteroids: beclomethasone, betamethasone, budesonide, cortisoneacetate, desoxymethasone, dexamethasone, fludrocortisone acetate,flunisolide, flucortolone, fluticasone propionate, hydrocortisone,methylprednisolone, prednisolone, prednisone, triamcinolone.

Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide,chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone,spironolactone, triamterene.

Anti-parkinsonian agents: bromocriptine mesylate, lysuride maleate.

Gastro-intestinal agents: bisacodyl, cimetidine, cisapride,diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine,nizatidine, omeprazole, ondansetron HCl, ranitidine HCl, sulphasalazine.

Histamine H,-Receptor Antagonists: acrivastine, astemizole, cinnarizine,cyclizine, cyproheptadine HCl, dimenhydrinate, flunarizine HCl,loratadine, meclozine HCl, oxatomide, terrenadine.

Lipid regulating agents: bezafibrate, clofibrate, fenofibrate,gemfibrozil, probucol.

Nitrates and other anti-anginal agents: amyl nitrate, glyceryltrinitrate, isosorbide dinitrate, isosorbide mononitrate,pentaerythritol tetranitrate.

Nutritional agents: betacarotene, vitamin A, vitamin B₂, vitamin D,vitamin E, vitamin K.

Opioid analgesics: codeine, dextropropyoxyphene, diamorphine,dihydrocodeine, meptazinol, methadone, morphine, nalbuphine,pentazocine.

Sex hormones: clomiphenc citrate, danazol, ethinyloestradiol,medroxyprogesterone acetate, mestranol, methyltestosterone,norethisterone, norgestrel, oestradiol, conjugated oestrogens,progesterone, synthetic progestins (also referred to as progestogens),stanozolol, stibocstrol, tibolone, testosterone, esters of testosterone,including esters of oleic acid, linoleic acid, linolenic acid, stearicacid, myristic acid, lauric acid, palmitic acid, capric or decanoic acidoctanoic or caprylic acid, pelargonic acid, undecanoic acid, tridecanoicacid, pentadecanoic acid, and the branched chain, cyclic analogues ofthese acids, testosterone analogues such as methyl-nortestosterone, andcombinations thereof. Synthetic progestins include, for example,levonorgestrel, levonorgestrel butanoate, drospirenone, norethisterone,desogestrel, etonorgestrel and medroxyprogesterone.

Gonadotropin releasing hormone (GnRH) antagonists that are orallyactive.

Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine,mazindol.

Mixtures of hydrophobic drugs may, of course, be used wheretherapeutically effective. For example, the combination of testosteronepalmitate with an orally active inhibitor or Type I or Type II5α-reductase or the combination of testosterone palmitate with asynthetic progestin may be preferable in some embodiments.

Drug delivery systems of the present invention and compositionscomprising same, comprise a hydrophobic drug or drugs dissolved in alipophilic surfactant and a hydrophilic surfactant. A lipophilicsurfiactant as defined herein has a hydrophilic-lipophilic balance (HLB)less than 10, and preferably less than 5. A hydrophilic surfactant asdefined herein has an HLB of greater than 10. (HLB is an empiricalexpression for the relationship of the hydrophilic and hydrophobicgroups of a surface active amphiphilic molecule, such as a surfactant.It is used to index surfactants and its value varies from about 1 toabout 45. The higher the HLB, the more water soluble the surfactant.)

According to one aspect of the present invention, each of the componentsof the delivery system (I.e., the lipophilic and hydrophilicsurfactants) individually have solvent characteristics and contribute,in part, to solubilizing the active ingredient. Those lipophilicsurfactants that contribute substantially to dissolving the drug aredefined herein as a “primary” solvent. Primary solvents can also provide“sustained-release” or “controlled-release” characteristics to the drugdelivery system. “Secondary” solvents are hydrophilic surfactants thatalso solubilize the drug, albeit to a lesser extent than a primarysolvent. In addition to dissolving the drug, secondary solventsfacilitate the dispersion of the delivery system in aqueous media orintestinal fluids and subsequent release of the drug. In cases where thesecondary solvent is a high melting point hydrophilic surfactant, it canalso provide for a sustained drug release, acting synergistically withthe lipophilic surfactant.

A hydrophilic surfactant component may be necessary to achieve desirableemission of the drug from within the formulation. That is, a hydrophilicsurfactant may be required to free the drug from within the lipidcarrier matrix, or primary solvent. In this respect, a high HLBsurfactant, such as Cremophor RH40, can generally suffice. In someformulations incorporating high levels of solubilized TP, the inventorshave observed that in the absence of a high HLB surfactant, there can besubstantially no release of the drug from blends solely comprisinglipophilic surfactants. The levels of the high HLB surfactant can beadjusted to provide optimum drug release without compromising thesolubilization of the active ingredient.

The lipophilic surfactant component, in some embodiments, may furthercomprise a “controlled-release” surfactant. In other words, in additionto being a solvent for the drug, the lipophilic surfactant may alsoprovide a semi-solid and sustained release (SR) matrix. Manysemi-solid/SR excipients are available to one of ordinary skill in theart, but those that additionally are good solvents for the drug aredesirable in the instant invention. Thus, preference should be given tosemi-solid lipid excipients having high solubilization potential for thedrug. In one aspect, “controlled-release” lipophilic surfactants exhibita melting point of about 25° C. to about 80° C., preferably about 35° C.to about 65° C., and more preferably 40 OC to about 60° C.

To be sure, however, “controlled-release” surfactants need not belimited to lipophilic surfactants alone. Indeed, some hydrophilicsurfactants in compositions of the instant invention may also providecontrolled-release characteristics in conjunction with a lipophilicsurfactant.

Lipophilic surfactants suitable in drug delivery systems of the presentinvention include:

Fatty acids (C₆-C₂, preferably C₁₀-C₂₄, more preferably C₁₄-C₂₄), forexample, octanoic acid, decanoic acid, undecanoic acid, lauric acid,myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid,and linolenic acid. Stearic acid and palmitic acid are preferred.

Mono- and/or di-glycerides of fatty acids, such as Imwitor 988 (glycerylmono-/di-caprylate), Imwitor 742 (glyceryl mono-di-caprylate/caprate),Imwitor 308 (glyceryl mono-caprylate), Imwitor 191 (glycerylmono-stearate), Softigen 701 (glyceryl mono-/di-ricinoleate), Capmul MCM(glyceryl caprylate/caprate), Capmul MCM(L) (liquid form of Capmul MCM),Capmul GMO (glyceryl mono-oleate), Capmul GDL (glyceryl dilaurate),Maisine (glyceryl mono-linoleate), Peceol (glyceryl mono-oleate),Myverol 18-92 (distilled monoglycerides from sunflower oil) and Myverol18-06 (distilled monoglycerides from hydrogenated soyabean oil),Precirol ATO 5 (glyceryl palmitostearate) and Gelucire 39/01(semi-synthetic glycerides, i.e., Cz₂-s mono-, di- and tri-glycerides).The preferred members of this class of lipophilic surfactants are thepartial glycerides of oleic, palmitic and stearic acids and blendsthereof.

Acetic, succinic, lactic, citric and/or tartaric esters of mono- and/ordi-glycerides of fatty acids, for example, Myvacet 9-45 (distilledacetylated monoglycerides), Miglyol 829 (caprylic/capric diglycerylsuccinate), Myverol SMG (mono/di-succinylated monoglycerides), Imwitor370 (glyceryl stearate citrate), Imwitor 375 (glycerylmonostearate/citrate/lactate) and Crodatem T22 (diacetyl tartaric estersof monoglycerides).

Propylene glycol mono- and/or di-esters of fatty acids, for example,Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene glycolmonomyristate), Captex 200 (propylene glycol dicaprylate/dicaprate),Miglyol 840 (propylene glycol dicaprylate/dicaprate) and Neobee M-20(propylene glycol dicaprylate/dicaprate).

Polyglycerol esters of fatty acids such as Plurol oleique (polyglyceryloleate), Caprol ET (polyglyceryl mixed fatty acids) and Drewpol 10.10.10(polyglyceryl oleate).

Castor oil ethoxylates of low ethoxylate content (HLB<l0) such as Etocas5 (5 moles of ethylene oxide reacted with 1 mole of castor oil) andSandoxylate 5 (5 moles of ethylene oxide reacted with 1 mole of castoroil.

Acid and ester ethoxylates formed by reacting ethylene oxide with fattyacids or glycerol esters of fatty acids (HLB<10) such as Crodet 04(polyoxyethylene (4) lauric acid), Cithrol 2MS (polyoxyethylene (2)stearic acid), Marlosol 183 (polyoxyethylene (3) stearic acid) andMarlowet G12DO (glyceryl 12 EO dioleate). Sorbitan esters of fattyacids, for example, Span 20 (sorbitan monolaurate), Crill 1 (sorbitanmonolaurate) and Crill 4 (sorbitan mono-oleate).

Transesterification products of natural or hydrogenated vegetable oiltriglyceride and a polyalkylene polyol (HLB<10), e.g. Labrafil M1944CS(polyoxyethylated apricot kernel oil), Labrafil M2125CS(polyoxyethylated corn oil) and Gelucire 37/06 (polyoxyethylatedhydrogenated coconut). Labrafil M1944CS is preferred.

Alcohol ethyoxylates (HLB<10), e.g. Volpo N3 (polyoxyethylated (3) oleylether), Brij 93 (polyoxyethylated (2) oleyl ether), Marlowet LA4(polyoxyethylated (4) lauryl ether) and

Pluronics, for example, Polyoxyethylene-polyoxypropylene co-polymers andblock co-polymers (HLB<10) e.g. Synperonic PE L42 (HLB=8) and SynperonicPE L61 (HLB=3)

Mixtures of suitable lipophilic surfactants, such as those listed above,may be used if desired, and in some instances are found to beadvantageous. For instance, glycerol palmitate and glycerol stearateesters alone and in blends are preferred lipophilic surfactants andcontrolled-release matrices.

Of the lipophilic surfactants listed above, those suitable as a“controlled-release” component include, but are not limited to, stearicacid, palmitic acid, and their glycerol and PEG esters, Precirol AT05,Imwitor 191, Myverol 18-06, Imwitor 370, Imwitor 375, Caprol ET, Cithrol2MS, Marosol 183, Gelucire 39/01 and combinations thereof.

Any pharmaceutically acceptable hydrophilic surfactant (i.e., having anHLB value greater than 10) may be used in the present invention. Somenon-limiting examples include:

Polyoxyethylene sorbitan fatty acid derivates e.g. Tween 20(polyoxyethylene (20) monolaureate), Tween 80 (polyoxyethylene (20)monooleate), Crillet 4 (polyoxyethylene (20) monooleate) and Montanox 40(polyoxyethylene (20) monopalmitate). Tween 80 (Polysorbate 80) ispreferred.

Castor oil or hydrogenated caster oil ethoxylates (HLB>10), e.g.Cremophor EL (polyoxyethylene (35) castor oil), Cremophor RH40(polyoxyethylene (40) hydrogenated castor oil), Etocas 40(polyoxyethylene (40) castor oil), Nikkol HCO-60 (polyoxyethylcne (60)hydrogenated castor oil), Solutol HS-15 (polyethylene glycol 660hydroxystearate), Labrasol (caprylocaproyl macrogol-8 glycerides),α-tocopherol-polyethylene glycol-1000-succinate (TPGS) and ascorbyl-6palmitate. Cremophor RH40 is preferred.

Gelucires, preferably Gelucire 50/13 (PEG mono- and diesters of palmiticand stearic acids. (In reference to Gelucires, the first number (i.e.,50) corresponds to the melting point of the material and the second(i.e., 13) to the HLB number.)

Fatty acid ethoxylates (HLB>10), e.g. Myrj 45 (polyoxyethylene (8)stearate), Tagat L (polyoxyethylene (30) monolaurate), Marlosol 1820(polyoxyethylene (20) stearate) and Marlosol OL15 (polyoxyethylene (15)oleate). Myrj 45 is preferred.

Alcohol ethoxylates (HLB>10), e.g. Brij 96 (polyoxyethylene (10) oleylether), Volpo 015 (polyoxyethylene (15) oleyl ether), Marlowet OA30(polyoxyethylene (30) oleyl ether) and Marlowet LMA20 (polyoxyethylene(20) C₁₂-C₁₄ fatty ether).

Polyoxyethylene-polyoxypropylene co-polymers and block co-polymers(HLB>10), that are commercially available under the trade name Pluronicsor Poloxamers, such as Poloxamers 188 and 407 also known as Syperonic PEL44 (HLB=16) and Syperonic F127 (HLB=22), respectively.

Anionic surfactants e.g. sodium lauryl sulphate, sodium oleate andsodium dioctylsulphosuccinate.

Alkylphenol surfactants (HLB>10) e.g. Triton N-101 (polyoxyethylene(9-10) nonylphenol) and Synperonic NP9 (polyoxyethylene (9)nonylphenol).

Of the hydrophilic surfactants listed above, those suitable as a“controlled-release” surfactant include, but are not limited toGelucires of high HLB value, such as Gelucire 50/13.

As mentioned, in one aspect of the present invention, each of thecomponents of the delivery system (i.e., the lipophilic and hydrophilicsurfactants) individually has solvent characteristics and contributes,in part, to solubilizing the active ingredient. In this way, withoutbeing bound by or limited to theory, the present invention does notrequire additional solvents, such as additional digestible oils and/orcosolvents, but these may be optionally included in the inventivesystems and formulations.

A digestible oil is defined herein as an oil that is capable ofundergoing de-esterification or hydrolysis in the presence of pancreaticlipase in vivo under normal physiological conditions. Specifically,digestible oils may be complete glycerol triesters of medium chain(C₇-C₁₃) or long chain (C₁₄-C₂₂) fatty acids with low molecular weight(up to C₆) mono-, di- or polyhydric alcohols. Some examples ofdigestible oils for use in this invention thus include: vegetable oils(e.g., soybean oil, safflower seed oil, corn oil, olive oil, castor oil,cottonseed oil, arachis oil, sunflower seed oil, coconut oil, palm oil,rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil,sesame oil, avocado oil, almond, borage, peppermint and apricot kerneloils) and animal oils (e.g., fish liver oil, shark oil and mink oil).

As well, optional cosolvents suitable with the instant invention are,for example, water, short chain mono-, di-, and polyhydric alcohols,such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylenecarbonate, polyethylene glycol with an average molecular weight of about200 to about 10,000, diethylene glycol monoethyl ether (e.g., TranscutolHP), and combinations thereof.

Other optional ingredients which may be included in the compositions ofthe present invention are those which are conventionally used in theoil-based drug delivery systems, e.g. antioxidants such as tocopherol,tocopherol acetate, ascorbic acid, butylhydroxytoluene,butylhydroxyanisole and propyl gallate; pH stabilizers such as citricacid, tartaric acid, fumaric acid, acetic acid, glycine, arginine,lysine and potassium hydrogen phosphate; thickeners/suspending agentssuch as hydrogenated vegetable oils, beeswax, colloidal silicon dioxide,mannitol, gums, celluloses, silicates, bentonite; flavoring agents suchas cherry, lemon and aniseed flavors; sweeteners such as aspartame,acesulfane K, sucralose, saccharin and cyclamates; etc.

The relative proportions of the lipophilic surfactant and hydrophilicsurfactant in the preferred hydrophobic drug carrier system of thisinvention are, in general, not especially critical, save that theconcentration of lipophilic and hydrophilic surfactants must besufficient to solubilize the hydrophobic drug, yet release same both invitro and in vivo. It should be noted that in some embodiments of theinvention, one hydrophobic drug may serve as a lipid vehicle foranother. More specifically, for example, a testosterone ester may serveas a carrier for testosterone. Even more specifically, TP may serve as alipid vehicle for testosterone. As well, TP may serve, in someembodiments, as its own “controlled-release” vehicle, which may obviatethe need for additional “controlled-release” lipids mentioned above.

Generally, the following relative concentrations, by weight, arepreferred (the percentages are based on the total content of hydrophilicsurfactant and lipophilic surfactant(s)):

Hydrophilic surfactant: 5-60%, more preferably 15-45%, and mostpreferably 30-40% Lipophilic surfactant: 10-90%, more preferably 20-80%,and most preferably 30-60% Lipophilic “controlled-release” surfactant:1-40%, more preferably 2.5-30%, and most preferably 5-25%.

The concentration of drug in the final pharmaceutical formulation willbe that which is required to provide the desired therapeutic effect fromthe drug concerned, but generally will lie in the range 0.1% to 50% byweight, preferably between about 10% to 30% by weight, and mostpreferably about 10% and 20% by weight, based on the weight of the finalcomposition. However, in many instances, because the presentcompositions may have better bioavailability than known compositions ofthe drug concerned, the drug concentration may be reduced as comparedwith the conventional preparations without loss of therapeutic effect.With specific reference to testosterone therapy, the present inventorshave learned that the use of the palmitate ester of T, in particular, isdesirable. Indeed, once absorbed, the long and fully saturated chain ofthe fatty acid on T slows the rate of hydrolysis of the ester bond thusprolonging the circulation of the TP and consequently T. For example,formulations of the present invention (e.g., formulation nos. 50 and 54(below)) comprising TP have a T half-life of about 8-9 hours. Bycomparison, the half-life for T is about 30 minutes and that ofT-undccanoate is about 1.5 hours.

In other embodiments, formulations of the present invention may haveself-emulsifying properties, forming a fine emulsion upon dilution withaqueous media or intestinal fluids in vivo. In other words, theformulations may have high surfactant and lipid content designed foradequate dispersion upon mixing with an aqueous medium. Qualitativedescription of the self-emulsification property of the inventiveformulations can be visually observed during the dissolution of same invitro. On the other hand, quantitative measurements may be taken of theparticle size of the emulsified droplets using laser light scatteringand/or turbidity measurements in the dissolution medium by UV/VISspectrophotometer. Any of these methodologies are available and known toone of ordinary skill in the art.

The pharmaceutical compositions according to the present invention maybe liquid, semi-solid, or solid at ambient temperatures, but preferablyare presented as liquids or semi-solids. Solid preparations are definedas solid, powdered medicaments blended with powdered excipients anddirectly filled into hard gelatin or cellulose capsule or compressedinto a tablet. The instant invention, however, preferably comprises asolid, powdered medicament (e.g., TP) that is solubilized in thepresence of the lipid surfactant excipients (e.g., any combination ofthe lipophilic and hydrophilic surfactants noted above). Accordingly,the melting point of the surfactants used is one factor that candetermine whether the resulting composition will be liquid or semi-solidat ambient temperature. Particularly preferred compositions of thepresent invention are liquid or semi-solid oral unit dosage forms, morepreferably filled into hard or soft capsules, e.g. gelatin or cellulosecapsules. The technology for encapsulating lipid-based pharmaceuticalpreparations is well known to one of ordinary skill in the art. As theinventive delivery systems and formulations described herein are notlimited to any one encapsulation method, specific encapsulationtechniques will not be further discussed.

The drug carrier systems and pharmaceutical preparations according tothe present invention may be prepared by conventional techniques forlipid-based drug carrier systems. In a typical procedure for thepreparation of the preferred carrier systems of this invention, thelipophilic surfactant is weighed out into a suitable stainless steelvessel and the hydrophilic surfactant is then weighed and added to thecontainer. Mixing of the two components may be effected by use of ahomogenizing mixer or other high shear device. If the material is solidat room temperature, sufficient heat is applied to ensure melting andfluidity without chemical decomposition.

The lipophilic “controlled-release” surfactant is then added, ifdesired, to the two other components in the stainless steel vessel andmixed using the appropriate equipment. The hydrophobic drug is thenweighed and added to the combined lipid mixture and mixing continueduntil either a homogenous solution is prepared. The formulation may bede-aerated before encapsulation in either soft or hard capsules. In someinstances the fill formulation may be held at elevated temperature usinga suitable jacketed vessel to aid processing.

Returning now to the delivery of testosterone, in one embodiment of thepresent invention, drug delivery systems of the present invention may besuitable for testosterone therapy. Testosterone is the main endogenousandrogen in men. Leydig cells in the testes produce approximately 7 mgof testosterone each day resulting in serum concentrations ranging fromabout 300 to about 1100 ng/dL. Women also synthesize testosterone inboth the ovary and adrenal gland, but the amount is about one-tenth thatobserved in eugonadal men. The majority (about 98%) of circulatingtestosterone is bound to sex hormone binding globulin and isbiologically active only when released to the free form. The term “free”is thus defined as not being bound to or confined within, for example,biomolecules, cells and/or lipid matrices of the inventive formulationsdescribed herein. Generally, “free” medicaments described herein referto medicament that is accessible to metabolic enzymes circulating inserum.

While the present invention should not be limited to the delivery oftestosterone or any particular ester thereof, TP has been found to offerunique chemical and physical characteristics that make its usepreferable in some embodiments. The present inventors have learned thatthe palmitic acid ester of testosterone, in particular, can yieldsuperior bioavailability to that found with other equivalent esters(e.g., testosterone undecanoate (TU)). Without being held to or bound bytheory, it is believed that TP is superior, in part, to othertestosterone esters, because it has a particularly high log P comparedto similar analogs. (The log P for TP is greater than 9 compared to alog P for TU of about 6.5)

Consequently, TP absorbed into the bloodstream may passively diffuseinto red blood cells (RBCs) circulating in the blood. Specifically,because palmitic acid is both a significant component of the RBCmembrane and has been shown to be transported across this membrane, TPis better suited to be in an equilibrium with and pass said membrane. Inthis manner, some portion of the total concentration of free TP at anygiven time may be found within RBCs. Further, when confined to a RBC,any TP therein is shielded from the esterascs found in the serum. As theconversion of TP to testosterone is a direct consequence of esteraseactivity, greater inaccessibility to the esterases is expected toprolong the half-life of TP. For this reason, it is believed that theresidence time of TP in the blood is greater than that would be expectedfrom other saturated esters of shorter hydrocarbon chain-length.

What is more, the use of TP, in contrast to that for other orallyadministered testosterone esters, does not appear to dramaticallyelevate serum dihydrotestosterone (“DHT”) above physiological levels,which are typically about 1/10th that of testosterone (i.e., about 30 to100 ng/dL) in eugonadal men. Testosterone interacts with respectiveandrogen receptors either directly or following its conversion to DHTvia the action of 5α-reductase. DHT is a more potent androgen thantestosterone and its elevated levels are thought by some scientists toincrease the risk of prostate cancer. Elevated levels of DHT are a notedproblem with the administration of, for example, TU. In this way, TPprovides yet another unexpected advantage over other testosteroneesters.

Specific embodiments of the instant invention will now be described innon-limiting examples. Table 1 provides composition details of variousformulations of testosterone (T) or testosterone-esters (T-esters), inaccordance with the teachings of the instant invention. For calculationpurposes, 1 mg of T is equivalent to: 1.39 mg T-enanthate; 1.58 mgT-undecanoate; 1.43 mg T-cypionate, and 1.83 mg T-palmitate. TP is apreferred T-ester in some of the formulations listed below. Thecompositions details of Table 1 (mg/capsule and wt. percentage) arebased on 800 mg fill weight per ‘00’ hard gelatin capsule. However, attestosterone-ester amounts less than about 100 mg/capsule, theformulations may be proportionally adjusted for smaller total fillweights that would permit use of smaller hard gelatin capsules (e.g.,‘0’ size).

As well, it should be apparent to one of ordinary skill in the art thatmany, if not all, of the surfactants within a category (e.g.,lipophilic, hydrophilic, etc.) may be exchanged with another surfactantfrom the same category. Thus, while Table 1 lists formulationscomprising Labrafil M1944CS (HLB=3) and Precirol ATO5 (HLB=2), one ofordinary skill in the art should recognize other lipophilic surfactants(e.g., those listed above) may be suitable as well. Similarly, whileTable 1 lists formulations comprising Cremophor RH40 (HLB=13) andLabrasol (HLB=14), one of ordinary skill in the art should recognizeother hydrophilic surfactants (e.g., those listed above) may besuitable.

TABLE 1 Labrafil Precirol Cremophor ID T or T-ester M1944CS AT05 RH40Labrasol A 400 109.68 66.49 223.83 — 50.00% 13.71% 8.31% 27.98% — B 360120.64 73.14 246.21 — 45.00% 15.08% 9.14% 30.78% — C 320 131.61 79.79268.60 — 40.00% 16.45% 9.97% 33.57% — D 280 142.58 86.44 290.98 — 35.00%17.82% 10.80% 36.37% — E 240 153.55 93.09 313.36 — 30.00% 19.19% 11.64%39.17% — F 228.32 156.75 95.03 319.9 — 28.54% 19.59% 11.88% 39.99% — G200 164.52 99.74 335.75 — 25.00% 20.56% 12.47% 41.97% — H 160 175.48106.39 358.13 — 20.00% 21.94% 13.30% 44.77% — I 120 186.45 113.04 380.51— 15.00% 23.31% 14.13% 47.56% — J 80 197.42 119.69 402.90 — 10.00%24.68% 14.96% 50.36% — K 40 208.39 126.33 425.28 — 5.00% 26.05% 15.79%53.16% — L 20 213.87 129.66 436.47 — 2.50% 26.73% 16.21% 54.56% — M 400199.97 66.62 133.40 — 50.00% 25.00% 8.33% 16.68% — N 360 219.97 73.29146.74 — 45.00% 27.50% 9.16% 18.34% — O 320 239.97 79.95 160.08 — 40.00%30.00% 9.99% 20.01% — P 280 259.96 86.61 173.42 — 35.00% 32.50% 10.83%21.68% — Q 240 279.96 93.27 186.76 — 30.00% 35.00% 11.66% 23.35% — R228.32 285.8 95.22 190.66 — 28.54% 35.73% 11.90% 23.83% — S 200 299.9699.94 200.10 — 25.00% 37.49% 12.49% 25.01% — T 160 319.96 106.60 213.45— 20.00% 39.99% 13.32% 26.68% — U 120 339.95 113.26 226.79 — 15.00%42.49% 14.16% 28.35% — V 80 359.95 119.92 240.13 — 10.00% 44.99% 14.99%30.02% — W 40 379.95 126.59 253.47 — 5.00% 47.49% 15.82% 31.68% — X 20389.95 129.92 260.14 — 2.50% 48.74% 16.24% 32.52% — AA 400 109.79 66.55149.72 73.94 50.00% 13.72% 8.32% 18.72% 9.24% BB 360 120.77 73.21 164.6981.33 45.00% 15.10% 9.15% 20.59% 10.17% CC 320 131.75 79.87 179.66 88.7240.00% 16.47% 9.98% 22.46% 11.09% DD 280 142.73 86.52 194.64 96.1235.00% 17.84% 10.82% 24.33% 12.01% EE 240 153.70 93.18 209.61 103.5130.00% 19.21% 11.65% 26.20% 12.94% FF 228.32 156.91 95.12 213.98 105.6728.54% 19.61% 11.89% 26.75% 13.21% GG 200 164.68 99.83 224.58 110.9025.00% 20.69% 12.48% 28.07% 13.86% HH 160 175.66 106.49 239.55 118.3020.00% 21.96% 13.31% 29.94% 14.79% II 120 186.64 113.14 254.52 125.6915.00% 23.33% 14.14% 31.82% 15.71% JJ 80 197.62 119.80 269.50 133.0910.00% 24.70% 14.97% 33.69% 16.64% KK 40 208.60 126.45 284.47 140.485.00% 26.07% 15.81% 35.56% 17.56% LL 20 214.09 129.78 291.95 144.182.50% 26.76% 16.22% 36.49% 18.02% MM 400 81.62 94.47 223.91 — 50.00%10.20% 11.81% 27.99% — NN 360 89.78 103.92 246.30 — 45.00% 11.22% 12.99%30.79% — OO 320 97.94 113.37 268.69 — 40.00% 12.24% 14.17% 33.59% — PP280 106.10 122.81 291.08 — 35.00% 13.26% 15.35% 36.39% — QQ 240 114.27132.26 313.47 — 30.00% 14.28% 16.53% 39.18% — RR 228.32 116.65 135.02320.01 — 28.54% 14.58% 16.88% 40.00% — SS 200 122.43 141.71 335.86 —25.00% 15.30% 17.71% 41.98% — TT 160 130.59 151.16 358.25 — 20.00%16.32% 18.89% 44.78% — UU 120 138.75 160.60 380.64 — 15.00% 17.34%20.08% 47.58% — VV 80 146.91 170.05 403.04 — 10.00% 18.36% 21.26% 50.38%— WW 40 155.08 179.50 425.43 — 5.00% 19.38% 22.44% 53.18% — XX 20 159.16184.22 436.62 — 2.50% 19.89% 23.03% 54.58% —

Table 2 provides composition details of various TP formulations inaccordance with the teachings of the instant invention and FIG. 9provides in vitro dissolution of select formulations therein. TP may besynthesized through esterification of testosterone with palmitoylchloride in an acetone/pyridine mixture. Testosterone palmitate crude ispurified by filtration, crystallized from a methanol/methylene chloridemixture and washed with methanol. When necessary, recrystallization canbe done from heptane followed by washing

TABLE 2 Composition details (mg/capsule and wt. percentage)* Fill wt F.No. TP LBR PRC5 OA Peceol TPGS SO CRH40 L'sol M'tol (mg)**  1 228.32285.84 57 570 (40.0) (50.0) (10.0)  2 228.32 57 228 57 570 (40.0) (10.0)(40.0) (10.0)  3 228.32 171 114 57 570 (40.0) (30.0) (20.0) (10.0)  4228.32 171 114 57 570 (40.0) (30.0) (20.0) (10.0)  5 228.32 114 57 171570 (40.0) (20.0) (10.0) (30.0)  6 228.32 476 95.2 800 (28.5) (59.5)(11.9)  7 228.32 95.2 380.8 95.2 800 (28.5) (11.9) (47.6) (11.9)  8228.32 190.4 95.2 285.6 800 (28.5) (23.8) (11.9) (35.7)  9 228.32 285.8495.2 190.56 800 (28.5) (35.7) (11.9) (23.8) 10 228.32 190.56 190.56190.56 800 (28.5) (23.8) (23.8) (23.8) 11 228.32 190.56 95.2 190.56 95.2800 (28.5) (23.8) (11.9) (23.8) (11.9) 12 228.32 190.56 190.56 95.2 95.2800 (28.5) (23.8) (23.8) (11.9) (11.9) 13 228.32 190.56 190.56 95.2 95.2800 (28.5) (23.8) (23.8) (11.9) (11.9) 14 228.32 285 95.2 95.2 95.2 800(28.5) (35.7) (11.9) (11.9) (11.9) 15 228.32 285.84 20.0 265.6 800(28.5) (35.7) (2.50) (33.2) 16 228.32 285.84 20.0 40.0 225.6 800 (28.5)(35.7) (2.50) (5.00) (28.2) 17 228.32 285.84 80.0 205.6 800 (28.5)(35.7) (10.0) (25.7) 18 228.32 95.20 190.56 285.6 800 (28.5) (11.9)(23.8) (35.7) 19 228.32 133.08 88.672 450 (50.73) (29.57) (19.7) 20228.32 285.84 200.28 85.72 800 (28.5) (35.7) (25.0) (10.7) 21 228.32285.84 95.2 190.67 800 (28.5) (35.7) (11.9) (23.8) 22 228.32 240.33 65.7160.22 105.74 800 (28.5) (30.0) (8.2) (20.0) (13.2) 23 228.32 157.0295.2 320.45 800 (28.5) (19.6) (11.9) (40.0) 24 228.32 157.02 95.2 214.4105.74 800 (28.5) (19.6) (11.9) (26.8) (13.2) 25 228.32 157.02 65.6349.6 800 (28.5) (19.6) (8.2) (43.7) 26 228.32 157.02 40.0 375.2 800(28.5) (19.6) (5.0) (46.9) 57 182.65 229.35 20.0 368.0 800 (22.83)(28.7) (2.5) (46.0) 58 120.0 520.0 20.0 140.0 800 (15.0) (65.0) (2.5)(17.5) *TP: Testosterone palmitate; LBR: Labrafil M1944CS; PRC5:PrecirolATO5; OA: Refined Oleic acid; SO: Refined Soybean oil; TPGS:D-α-tocopheryl PEG1000 succinate; CRH 40: Cremophor RH40; L'sol:Labrasol; M'tol: Mannitol **Filled into size “0” capsule (570 mg) or“00” capsule (800 mg)

Component mg/capsule %, w/w Testosterone palmitate 228.32 28.5Cremophor ® RH40 320.45 40.0 Labrafil ® M 1944 CS 157.02 19.6 Precirol ®ATO 5 95.20 11.9 Total: 800 100.0

In some embodiments, it may be desirable to reduce the absoluteconcentration of testosterone and/or an ester thereof in order topromote a relatively faster release of the testosterone and/or esterfrom within the lipid vehicle. That is, it has been found, surprisingly,that reducing the concentration of TP, may in some cases, confer quickerrelease kinetics. For example, for significant release of TP withinabout a two hour period, a concentration of TP of less than about 23percent by weight. In some embodiment, a weight percentage of less thanabout 20 is preferred, more preferably a weight percentage of less thanabout 18, and most preferably a weight percentage of less than about 15.Without being bound by or limited to theory, it is believed that TP atlevels greater than about 23 weight percent may, in fact, retard its ownrelease. For example, formulations according to the instant inventioncomprising less than about 23 weight percent TP can release 50-70% ofthe drug at 1 hour and 80 to near 100% at 2 hours. On the other hand,formulations according to the instant invention comprising greater thanabout 23 weight percent TP release less than 5% of the drug at 1 hr andless than 70% at 6 hours.

Table 3 provides composition details of various TP formulations, that insome cases, are at TP concentrations lower than those in Table 2 and inaccordance with the teachings of the instant invention. FIG. 10 providesin vitro dissolution of select Table 3 formulations.

TABLE 3 Composition (mg/capsule and weight %) Fill Cremophor OleicCapmul Tween Precirol Gelucire Wt. F. No. TP Labrasol RH40 Acid MCM(L)80 ATO5 39/01 (mg) 27 320.0 — 240.0 220.0 — — 20.0    — 800 (40.0%)(30.0%) (27.5%) (2.5%) 28 364.0 — 160.0 80  176.0 — 20.0    800 (45.5%)(20.0%) (10.0%) (22.0%) (2.5%) 29 320.0 160.0 — — 300.0 — — 20.0    800 (40%)  (20%) (37.5%) (2.5%) 30, 34 120.0 — — — 680.0 — — — 800 (15.0%)(85.0%) 31, 35 120.0 — — — 560.0 120.0 — — 800 (15.0%) (70.0%) (15.0%)32 228.0 — 296.0  80.0 176.0 — 20.0    — 800 (28.5%) (37.0%) (10.0%)(22.0%) (2.5%) 33 228.0 240.0 — — 312.0 — — 20.0    800 (28.5%) (30.0%)(39.0%) (2.5%) 36 120.0 — 300.0 120.0 240.0 — 20.0    — 800  (15%)(37.5%) (15.0%) (30.0%) (2.5%) 37 120.0 300.0 — — 360.0 — — 20.0    800 (15%) (37.5%) (45.0%) (2.5%) 38 176.0 — — — 624.0 — — — 800 (22.0%)(78.0%  39 228.0 — — — 572.0 — — — 800 (28.5%) (71.5%) 40 176.0 — — —504.0 120.0 — — 800 (22.0%) (63.0%) (15.0%) 41 176.0 — 120.0 — 504.0 — —— 800 (22.0%)  (15%) (63.0%) 42 176.0 120.0 — — 504.0 — — 800 (22.0%)(15.0%) (63.0%) 43 120.0 680.0 — — — — — 800  (15%)  (85%) 44 120.0340.0 — — 320.0 — — 20.0    800  (15%) (42.5%) (40.0%) (2.5%) 45 120.0 —— 680.0 — — — — 800  (15%)  (85%) 46 120.0 — 680.0 — — — — — 800  (15%) (85%) 47 120.0 — 660.0 — — — — 20.0    800  (15%) (82.5%) (2.5%) 48176.0 120.0 — — 504.0 — — — 800 (22.0%) (15.0%) (63.0%) 49 120.0 — 408.0272.0 — — 800 (15.0%)  (51%)  (34%) 50 120.0 — —  370.48  246.88 — — —800  (15%) (46.31) (30.86%)  51 120.0 140.0 — — 520.0 — — 20.0    800 (15%) (17.5%) (65.0%) (2.5%) 52  182.65  97.36 520.0 800 (22.83%) (12.17%)  (65.0%) 53  182.65  97.36 208.0 312.0 800 (22.83%)  (12.17%)  (26%)  (39%) 54 120.0 — — 204.0 476.0 — — — 800  (15%) (25.5%) (59.5%)55  182.65 — —  185.21  432.15 — — — 800 (22.83%)  (23.15%)  (54.02%) 56  182.65 — —  185.21  81.28 — — — 800 (22.83%)  (67.01%)  (10.16%)  59120.0 — 320.0 — 340.0 — — 20.0    800  (15%)  (40%) (42.5%) (2.5%)

Formulation numbers 50, 51 and 54 are preferred embodiments. As well,while a variety of solvents may be useful in the formulations presentedin Table 3, preferred solvents may have the following characteristics:C₄-C₂₄ fatty acids and/or their glycerol-, propylene glycol-,polyethylene glycol, sorbitan-mono-/diesters alone and in mixtures.Preferred fatty acids and esters are C₈-C₁₈, saturated and unsaturated.In addition, the solvents include, fatty acid esters with loweralcohols, such as ethyl oleate, ethyl linoleate, isopropyl myristate,isopropylpalmitate, isopropyloleate and isopropyllinoleate.

EXAMPLE

Formulations 50 and 54 were administered to 6 patients; number 50 wasadministered once-daily (“QD”) in the form of two capsules per dose (100mg T equivalents/capsule) and number 54 was administered once- andtwice-daily (“BID”) in the form of three capsules per dose (66 mg Tequivalents/capsule). The mean steady-state profiles after 7 days oftreatment with one of the three, respective, regimens are shown in FIG.11. The pharmacokinetic profile for formulation 54 BID was relativelyuniform over the entire 24 hr period and had a trough of the meanprofile about 70% of the peak of the mean profile. Additional data fromformulation 54 include:

-   -   Average serum T increase from baseline of 275 ng/dL    -   Mean serum T levels at lower end of normal range, i.e., about        325 ng/dL.    -   Relatively fast release (T_(max) of about 1 hour)    -   Estimated terminal half-life of T at steady-state of        approximately 8-9 hours    -   Consistent dose-related elevation in serum T baseline levels        over the 7-day treatment period    -   Average steady-state serum DHT level of 114 ng/dL (FIG. 12)

A simulation of the pharmacokinetic profile of formulation 50administered BID was performed and compared to the observed profile forformulation 54 administered BID. The simulation predicts about a 384ng/dL increase in C_(avg) over the 24-hour period for formulation 50over formulation 54 (FIG. 13).

In other embodiments of the present invention, methods and compositionsfor modulating (i.e., sustaining) the rate of available serumtestosterone by incorporating component(s) that may biochemicallymodulate (1) TP absorption, (2) TP metabolism to T, and/or (3)metabolism of T to DHT. For example, the inclusion of medium to longchain fatty acid esters can enhance TP absorption. Without being held toor bound by theory, the present inventors believe that the use ofeffective amounts fatty acid esters, particularly palmitate esters suchas ascorbyl-palmitate, retinyl-palmitate, sorbitan-palmitate and blendsthereof may establish competition between said ester and TP forendogenous esterase activity. Indeed, it is believed that testosteroneester metabolism, generally, may be retarded with the administration ofan effective amount of an ester of a medium or long chain fatty acid(e.g., esters of oleic acid, linoleic acid, linolenic acid, stearicacid, myristic acid, lauric acid, palmitic acid, capric or decanoic acidoctanoic or caprylic acid, pelargonic acid, undecanoic acid, tridecanoicacid, pentadecanoic acid, and the branched chain, cyclic analogues ofthese acids). In this way, more TP may stave off hydrolysis in the gutand enter the blood stream. In other words, the fatty acid ester maycompetitively inhibit esterases that would otherwise metabolize TP.Table 4 provides effective amounts of inhibitors of testosterone estermetabolism. Examples of other esters or combinations thereof includebotanical extracts or benign esters used as food additives (e.g.,propylparben, octylacetate, and ethylacetate).

Other components that can modulate TP absorption include “natural” andsynthetic inhibitors of 5α-reductase, which is present in enterocytesand catalyze the conversion of T to DHT. Complete or partial inhibitionof this conversion may both increase and sustain increases serum levelsof T after oral dosing with TP while concomitantly reducing serum DHTlevels. Borage oil, which contains a significant amount of the5α-reductase inhibitor gamma-linoleic acid (GLA), is an example of a“natural” modulator of TP metabolism. Other than within borage oil, ofcourse, GLA could be directly added as a separate component of TPformulations described herein. Many natural inhibitors of 5α-reductaseare known in the art (e.g., epigallocatechin gallate, a catechin derivedprimarily from green tea and saw palmetto extract from berries of theSerenoa repens species), all of which may be suitable in the presentinvention. Non-limiting examples of synthetic 5α-reductase inhibitorssuitable in the present invention include finasteride and dutasteride.

In addition to 5α-reductase inhibitors, the present inventioncontemplates the use of inhibitors of T metabolism via other mechanisms.One such point of inhibition may be the cytochrome P450 isozyme CYP3A4that is present in enterocytes and in liver cells and thus capable ofmetabolizing testosterone. Accordingly, formulations of the presentinvention, in some embodiments, include peppermint oil, which is knownto contain factors capable of inhibiting CYP3A4.

Table 4 provides composition details of various TP formulationscomprising ingredients to modulate TP absorption (i.e.,ascorbyl-palmitate, borage oil and peppermint oil). FIGS. 14 and 15 showrepresentative in vitro dissolution profiles for select TP formulationstherein in either phosphate buffer (PBS) or fed-state simulatedintestinal fluid (FeSSIF), respectively.

TABLE 4 Composition % w/w (mg/“00” capsule)¹ Fill Ascorbyl- CremophorCremophor Oleic Borage Peppermint Wt. F. No. TP Palmitate RH40 EL AcidPeceol Oil Oil (mg)² 62 30.0 2.5 — — 67.5 — — — 800 (240) (20) (540) 62A15.0 2.5 — — 82.5 — — — 800 (120) (20) (660) 63 30.0 5.0 — — 65.0 — — —800 (240) (40) (520) 63A 22.9 5.0 12.2 — 60.0 — — — 800 (183) (40)  (97)(480) 64 15.0 15.0  — — 70.0 — — — 800 (120) (120) (560) 64A 15.0 10.0 25.0 — 50.0 — — — 800 (120) (80) (200) (400) 65 22.9 — 25.0 — 52.0 — — —800 (183) (200) (417) 66 15.0 — 42.5 — — 42.5 — — 800 (120) (340) (340)67 15.0 — 30.0 — — 55.0 — — 800 (120) (240) (440) 68 22.9 — 20.0 — 45.012.0 — — 800 (183) (160) (360)  (96) 69 22.9 — — — 53.0 19.0 — — 800(183) (424) (152) 70 22.9 10.0  25.0 — 22.1 — 10.0 10.0  800 (183) (80)(200) (177) (80) (80) 70B 22.9 2.5 20.0 — 39.7 — 10.0 5.0 800 (183) (20)(160) (318) (80) (40) 71 15.0 10.0  25.0 — 30.0 — 10.0 10.0  800 (120)(80) (200) (240) (80) (80) 71A 10.0 2.5 20.0 — 52.5 — 10.0 5.0 800 (80)(20) (160) (420) (80) (40) 71B 15.0 2.5 20.0 — 47.5 — 10.0 5.0 800 (120)(20) (160) (380) (80) (40) 72 15.0 — 60.0 — 25.0 — — — 800 (120) (480)(200) 73 15.0 — — 60.0 25.0 — — — 800 (120) (480) (200) ¹Milligramweights rounded to nearest whole number ²±1 mg

In yet another embodiment of the present invention, drug deliverysystems disclosed herein may also be suitable for ameliorating some ofthe side-effects of certain strategies for male contraception. Forexample, progestin-based male contraception substantially suppressesluteinizing hormone (LH) and follicle-stimulating hormone (FSH), andthereby suppresses spermatogenesis, resulting in clinical azoospermia(defined as less than about 1 million sperm/ml semen for 2 consecutivemonths). However, administration of progestins also has the undesirableside-effect of significantly reducing steady-state serum testosteronelevels.

In such situations, for example, it may be preferable to providepreparations of progestin concomitantly with testosterone or atestosterone derivative (e.g., TP). More preferably, a pharmaceuticalpreparation according to the invention is provided, comprisingprogestin—in an amount sufficient to substantially suppress LH and FSHproduction—in combination with testosterone. In some embodiments, thepharmaceutical preparation is for once-daily, oral delivery.

Drug delivery systems, in one aspect of the present invention, affordthe flexibility to achieve desirable pharmacokinetic profiles.Specifically, the formulations can be tailored to deliver medicament ina relatively early peak serum concentration (T_(max)) or one thatappears later. See FIGS. 1, 3, 5 and 7 versus FIGS. 2, 4, 6 and 8,respectively. Similarly, the formulations may be tailored to have arelative steep or wide drop in drug serum concentration upon obtainingT_(max). See FIGS. 1, 3, 5 and 7 versus FIGS. 2, 4, 6 and 8,respectively. Accordingly, pharmaceutical preparations of the instantinvention may be administered once-daily, twice-daily, or in multipledoses per day, depending on, for example, patient preference andconvenience.

One way in which the formulations may be modified to affect thesechanges is to calibrate the ratio of lipophilic surfactants. Themagnitude and timing of the T_(max), for example, can be affected by notonly the type of lipids used, but also the ratios thereof. For example,to obtain a relatively early T_(max), or fast release of the medicamentfrom the delivery system, the concentration of the “controlled-release”lipophilic surfactant (e.g., Precirol) may be reduced relative to theconcentration of the other lipophilic solvents (e.g., Labrafil M1944CS).On the other had, to achieve a delayed T_(max), the percentage of“controlled-release” lipophilic surfactant in composition can beincreased. FIGS. 9 and 10 show in vitro dissolution curves of TP fromthree formulations, respectively, in a phosphate buffered dissolutionmedium incorporating TritonX-100 as a surfactant in accordance with thepresent invention.

Without being bound by or limited to theory, it is believed that theinventive formulations described herein, in one aspect, enhanceabsorption of a medicament therein by the intestinal lymphatic system.In this way, drug delivery systems of the present invention can provideextended release formulations that can deliver testosterone into theserum over several hours. The serum half-life of testosterone in men isconsidered to be in the range of 10 to 100 minutes, with the upper rangefor testosterone administered in a form (i.e., TU) that favors lymphaticabsorption. However, oral dosages of the present invention can be takenby a patient in need of testosterone therapy once every about twelvehours to maintain desirable levels of serum testosterone. In a morepreferred embodiment, oral dosages are taken by a patient in need oftestosterone therapy once every about twenty four hours. In general,“desirable” testosterone levels are those levels found in a humansubject characterized as not having testosterone deficiency.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or alterations of the invention following. In general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth and as follows in the scope ofthe appended claims.

The invention claimed is:
 1. A method of treating a hypogonadal humanmale with testosterone deficiency comprising orally administering to ahuman male in need thereof an oral pharmaceutical composition comprising15-20 percent by weight of solubilized testosterone undecanoate, 5-20percent by weight of hydrophilic surfactant, wherein the formulationconsists of a liquid or semi-solid encased in a capsule, wherein saidadministration is twice daily, and wherein the administration providesan average serum concentration of testosterone at steady state of about300 ng/dl to about 1100 ng/dl.
 2. The method as recited in claim 1,wherein said the hydrophilic surfactant exhibits an HLB of 10 to
 45. 3.The method of claim 2, in which the hydrophilic surfactant is chosenfrom polyoxyethylene sorbitan fatty acid esters, hydrogenated castor oilethoxylates, PEG mono- and di-esters of palmitic and stearic acids,fatty acid ethoxylates, and combinations thereof.
 4. The method of claim3, in which the hydrophilic surfactant is a hydrogenated castor oilethoxylate.
 5. The method of claim 1, wherein the formulation is aliquid encased in a capsule.
 6. The method of claim 1, wherein theformulation is a semi-solid encased in a capsule.